Process for the preparation of amorphous form of torsemide

ABSTRACT

The present invention relates to a simple and efficient process for the preparation of amorphous form of torsemide, demonstrated in the X-ray diffraction pattern of FIG.  1.

FIELD OF THE INVENTION

[0001] The present invention relates to a simple and efficient processfor the preparation of amorphous form of torsemide.

BACKGROUND OF THE INVENTION

[0002] Chemically, torsemide is1-isopropyl-3-[(4-m-toludino-3-pyridyl)-sulphonyl]urea and has thestructural formula I.

[0003] Torsemide is used for the treatment of hypertension and edemaassociated with congestive heart failure, renal disease or hepaticdisease. Torsemide is a loop diuretic whose primary site of action isthe ascending limb of the loop of Henle. It has a sustained duration ofaction unlike standard loop diuretics. It is also used in the treatmentof hypertension.

[0004] Torsemide has been reported to exist in different polymorphicforms. It is known that different morphs of biologically activecompounds may have different absorption profile in vivo and consequentlydifferent pharmacokinetic profile. An amorphous form of torsemide hasrecently been disclosed in the PCT application, WO 01/10441. The processinvolves dissolving torsemide in water using ammonia gas or ammoniumhydroxide, cooling the solution and isolating the amorphous torsemide bylyophilization or freeze drying. The process is unsuitable forindustrial use as it involves cooling to low temperatures in the rangeof −50° to −80° C. and use of expensive techniques such aslyophilization or freeze drying. The process also involves the use ofpotentially hazardous ammonia gas and has the disadvantage of takingupto 80 hours thus rendering it uneconomical.

SUMMARY OF THE INVENTION

[0005] It is an objective of the present invention to provide anefficient method for the preparation of amorphous form of torsemide. Theprocess does not involve drastic conditions of temperature or prolongedoperations and is thus convenient to operate on a commercial scale andis operationally safe.

[0006] Accordingly, the present invention provides a process for thepreparation of amorphous form of torsemide which comprises recoveringamorphous torsemide from a solution thereof in a suitable solvent byspray drying.

[0007] The solution of torsemide may be obtained by dissolvingcrystalline torsemide in a suitable solvent or alternatively such asolution may be obtained directly from a reaction mixture in whichtorsemide is formed in a suitable solvent. The term “suitable solvent”includes alcohols, ketones, chlorinated hydrocarbons, esters, nitrites,cyclic ethers, and mixture(s) thereof. Examples of alcohol includemethanol, ethanol, isopropanol, and the like. Examples of ketone includeacetone, methyl isobutyl ketone and the like. Examples of chlorinatedhydrocarbons include dichloromethane, dichloroethane, and the like.Examples of ester include methyl acetate, ethyl acetate, butyl acetateand the like. Example of nitrile include acetonitrile, and the like.Examples of cyclic ethers include tetrahydrofuran, dioxane, and thelike.

[0008] The crystalline torsemide used as a starting material may be anyof the various polymorphic forms known in the prior art such asmodification I, modification II, modification III, form V, dupont formI, dupont form II etc. as disclosed in patents/patentapplications/publications: U.S. Re30,633, U.S. Re34,580, U.S. Pat. No.6,166,045, WO 00/20395, WO 01/10441, Acta Cryst., 2659 (1975) and ActaCryst., 1304 (1978).

[0009] The spray drying may be accomplished using a spray dryer whichoperates on the principle of nozzle spraying in a parallel flow, i.e.the sprayed product and the drying gas flow in the same direction. Thedrying gas can be air or inert gases such as nitrogen, argon or carbondioxide. Nitrogen is preferred in this case.

[0010] The amorphous torsemide prepared according to the process of thepresent invention was characterized by its X-ray powder diffraction, asshown in FIG. 1, pattern which gave a plain halo and showed no peaks,thus demonstrating the amorphous nature of the product.

DETAILED DESCRIPTION OF THE INVENTION

[0011] The present invention is further illustrated by the followingexample, which is not intended to limit the scope of this invention inany way.

EXAMPLE

[0012] Preparation of Amorphous Form of Torsemide

[0013] Crystalline torsemide (3.0 g) was dissolved in acetone (540 ml)at 45-50° C. The clear solution thus obtained was subjected to spraydrying in a Mini Spray Dryer (Model Buchi-190) with an inlet temperatureof 75-77° C. and an outlet temperature of 52-58° C. The fine powder oftorsemide in an amorphous form was collected. It was further dried undervacuum at 30-35° C. to yield 1.8 g of torsemide of amorphous form. X-raypowder diffraction pattern showed a plain halo which demonstrates theamorphous nature of the product (FIG. 1).

[0014] While the present invention has been described in terms of itsspecific embodiments, certain modifications and equivalents will beapparent to those skilled in the art and are intended to be includedwithin the scope of the present invention.

1. A process for the preparation of amorphous form of torsemide whichcomprises recovering amorphous torsemide from a solution thereof in asuitable solvent by spray drying.
 2. The process of claim 1 wherein thesolution is obtained directly from a reaction mixture in which torsemideis formed in a suitable solvent.
 3. The process of claim 1 wherein thesolution is obtained by dissolving crystalline torsemide in a suitablesolvent.
 4. The process of claim 1 to 3 wherein the suitable solventincludes alcohols, ketones, chlorinated hydrocarbons, esters, nitrites,cyclic ethers, and mixtures thereof.
 5. The process of claim 4 whereinthe solvent is selected from the group consisting of methanol, ethanol,isopropanol, acetone, methyl isobutyl ketone, dichloromethane,dichloroethane, ethylacetate, methylacetate, butylacetate, acetonitrile,tetrahydrofuran, dioxane, and mixtures thereof.